Objectives of the current RFA include elucidating the "identity, locus and functional characteristics of glucose sensing neurons", understanding "the relative roles and interactions of peripheral and central glucose sensing", and determining "how these are altered with recurrent hypoglycemia". While two important loci for hypoglycemic detection have been identified, the brain and portal vein, the specific neurons involved, the mechanism(s) by which they detect ambient glycemia, and how afferent input from these two critical loci is integrated remain to be fully elucidated. Our long-term goal is to elucidate the mechanisms of peripheral hypoglycemic detection, providing insight towards more effective treatment of diabetes. In the current proposal we focus on the portal vein glucosensors. We provided the first physiological evidence that glucosensors in the portohepatis were important for the sympathoadrenal response to hypoglycemia. Subsequently we constrained the glucosensing locus to the portal vein and demonstrated the essential role of portal vein innervation. In the Preliminary Results we provide new evidence that the neurons involved in portal glucose sensing are spinal in origin (not vagal), capsaicin sensitive, and respond to alternative fuels, e.g. lactate. In the current proposal we will employ selective denervation procedures and the "local irrigation technique"(developed in our lab) to address the following specific aims: 1) to identify the origin, axis and type of neurons involved in for portal vein glucose sensing, 2) ascertain the relative contribution of portal vein vs. CNS glucosensors towards hypoglycemic detection under conditions of varying rates of glycemic decline, and 3) to quantify the impact of recurrent hypoglycemia upon portal glucosensing and elucidate the mechanism(s) underlying this impairment.